Viruses cause an array of disease manifestations ranging from acute respiratory disease, intestinal diarrhea, hemorrhagic fevers, hepatitis, cancer, and chronic autoimmune disease and in some instances death. One virus that was recently identified to be associated with cancer in humans in 1995 is human herpesvirus 8 (HHV8)/Kaposi's sarcoma-associated herpesvirus (KSHV). An accumulation of scientific evidence now substantiates HHV8 as the etiological agent responsible for classical and acquired immunodeficiency disease syndrome (AIDS)-related Kaposi's sarcoma (KS), as well as other lymphoproliferative disorders (LPDs) in immunocompetent and human immunodeficiency virus (HIV)-infected humans. Despite all of this scientific evidence it is difficult to fully understand how the virus causes disease without the ability to follow a natural infection. As such, alternative in vivo models that are readily accessible and can recapitulate HHV8 infection and associated disease are absolutely needed to identify viral determinants of pathogenesis and how these specific determinants, either viral open reading frames (ORFs) or other viral-encoded macromolecules are involved in HHV8-mediated pathogenesis. Here, we propose to utilize a closely related and relevant virus that can manifest similar biological outcomes in its natural host. The genome of the virus, referred to as rhesus rhadinovirus (RRV) has been characterized and shown to be essentially colinear and encodes most of the viral ORFs thought to be associated with pathogenesis. More importantly, in vivo studies show that RRV infection in its natural host recapitulates many, if not most of the properties of HHV8, including persistence and LPDs. The long term goals of the proposed research project are to better understand how HHV8 interacts with its host, utilizing RRV and experimental infection its natural host. This will be accomplished by a series of experimental in vivo infections and characterization of the host immune response. Additionally, the role of specific ORFs of RRV will be interrogated by creating a number of defined recombinants utilizing the RRV-bacterial artificial chromosome (RRV-BAC) that we successfully generated and shown to be infectious and pathogenic. Combining these types of in vitro and in vivo to address viral pathogenesis will enable researchers to dissect how viruses cause infection and disease in susceptible populations and how scientists can shift the pendulum in favor of the host.